The long-term objective of this research is to develop a bioerodible, ointmentlike polymer for use in the treatment of periodontitis. This delivery system will be capable of releasing a therapeutic agent by an erosion-controlled process, with kinetics approaching zero order, from within the periodontal pocket. The therapeutic agent (for example, tetracycline) is incorporated by direct mixing into a poly (ortho ester) ointmentlike polymer that contains hydrolytically labile linkages. Release of the medicament is controlled by a combination of diffusion and the rate at which these linkages cleave. Because poly (ortho esters) are acid sensitive, the rate of hydrolysis can be controlled by means of incorporated acidic excipients. In addidon, the rate of hydrolysis increases as the hydrophilicity of the polymer increases. Thus, the rate of polymer hydrolysis and consequent drug release can be fairly precisely controlled. The easy incorporation of the therapeutic agent of interest, whether it is a small molecule such as an antibacterial agent or a macromolecule such as a peptide or protein, affords a delivery system that can deliver a range of medicaments from within the periodontal pocket. This study will develop such a system and evaluate all aspects of its release and delivery, efficacy, and toxicity. Once a working polymeric ointment has been developed, it will be characterized by extensive studies evaluating in vitro drug delivery rate and the ability of the candidate ointments to adhere to moist tooth surfaces. Mutagenicity, acute oral and intravenous toxicity, and oral subchronic toxicity testing will be performed; and mucosal irritancy and limited efficacy studies will be conducted using beagle dogs with plaque induced periodontitis. In the efficacy study in beagle dogs, the tetracycline-loaded polymeric ointment will be delivered by syringe to the periodontal pocket, and clinical efficacy assessments-including the plaque index, gingival index, probing loss of attachment, and probing pocket depth-win be made. Following treatment, gingival crevicular fluid saples will be collected with filter paper strips (Periopaper) placed at the pocket orifice. These crevicular fluid samples will be evaluated for their tetracycline content and in vitro antibacterial activity against selected anaerobic organisms.